Depression is a widespread disease, with high mortality
and recurrence
rates. Recent studies have shown that elevated cytokine levels are
implicated in the molecular mechanisms of depression. Oxidative stress
contributes to the stimulation of cytokine production. Growing evidence
suggests that ginsenoside Re (Gs-Re) exerts a neuroprotective effect
on the hippocampus by suppressing oxidative stress and inflammation.
However, the effect and mechanism of Gs-Re in the treatment of depression
remain understudied. This study aimed to evaluate the neuroprotective
and antidepressant-like effects of Gs-Re and the possible underlying
mechanisms. In this article, the antidepressant-like effect of the
Gs-Re was studied both in vitro (H2O2-induced
oxidative stress in HT-22 cells) and in vivo (reserpine-induced depressive
model mice). Our results indicated that, at the cellular level, Gs-Re
effectively enhanced cell survival following H2O2 stimulation, inhibited the mass production of oxidative stress markers
(MDA and ROS), and prevented the occurrence of apoptosis. Moreover,
Gs-Re significantly reduced the levels of proinflammatory cytokines
IL-1β, IL-6, and TNF-α and restored the abnormal mitochondrial
membrane potential. Subsequently, Gs-Re treatment reversed reserpine-induced
neuroinflammation and depressive-like behaviors in vivo and inhibited
microglia overactivation. Furthermore, the alterations in the BDNF/TrkB/ERK/CREB
signaling pathway induced by H2O2 or reserpine
in HT-22 cells or in the mouse hippocampus were significantly reversed
by Gs-Re. K252a blocked the improvement of Gs-Re on depression-like
behavior and eliminated the inhibition of oxidative stress and neuroinflammation
in vivo. This study suggested that Gs-Re produces neuroprotective
and depressive effects by inhibiting oxidative stress and inflammation
and activating the BDNF/TrkB/ERK/CREB pathway.